Method for producing  3,4-dihydroisoquinoline derivatives and production intermediates of same

ABSTRACT

Provided are an efficient method for producing 3,4-dihydroisoquinoline derivatives and useful production intermediates thereof. Provided is a method for producing 3,4-dihydroisoquinoline derivatives represented by general formula (1), comprising converting a compound represented by general formula (3) in the presence of acid after reacting with an aniline derivative, or converting a compound represented by general formula (3) by reacting with an aniline derivative in the presence of an acid.

TECHNICAL FIELD

The present invention relates to a method for producing3,4-dihydroisoquinoline derivatives and production intermediatesthereof.

BACKGROUND ART

Numerous chemicals have been proposed for the purpose of controllingdiseases in agricultural and horticultural crops. For example, a3,4-dihydroisoquinoline derivative represented by general formula (1):

wherein R1 and R2 independently represent an optionally substitutedalkyl group having 1 to 6 carbon atoms or R1 and R2 together with thecarbon atom to which they are bound form an optionally substitutedcycloalkyl group having 3 to 10 carbon atoms, X represents a halogenatom, optionally substituted alkyl group having 1 to 6 carbon atoms oroptionally substituted alkoxy group having 1 to 6 carbon atoms, nrepresents an integer of 0 to 4, Y represents a halogen atom, optionallysubstituted alkyl group having 1 to 6 carbon atoms or optionallysubstituted alkoxy group having 1 to 6 carbon atoms, and m represents aninteger of 0 to 4, is disclosed in Patent Document 1 as being useful asan agricultural and horticultural microbicide. Moreover, a group ofcompounds derived from a compound represented by general formula (1) arealso effective as agricultural and horticultural microbicides, and thesecompounds can also be intermediates for the production of agriculturaland horticultural microbicides (Patent Document Nos. 1 and 2).Consequently, being able to produce these compounds both simply andefficiently is an extremely important issue.

According to Patent Document 1, a compound represented by generalformula (1) is disclosed as being able to be prepared by using a3-cyanoquinoline derivative as a starting material and reacting with aphenethyl alcohol derivative or styrene derivative, thus demonstratingthat a 3-cyanoquinoline derivative is an important raw material.

An examination of the prior art relating to 3-cyanoquinoline revealsthat it is produced by methods such as: (I) a method in which3-bromoquinoline and copper cyanide are reacted at 250° C. (Non-PatentDocument 1), (II) a method in which 2-dimethoxymethylacrylonitrile andaniline are reacted followed by converting with aluminum chloride(Non-Patent Document 2), (III) a method in which4-nitroquinoline-1-oxide and potassium cyanide are reacted followed bychlorinating with phosphorous oxychloride and further subjecting tocatalytic hydrogenation using palladium as catalyst (Non-Patent Document3) for conversion, (IV) a method in which 3-bromoquinoline, sodiumcyanide, potassium iodide, copper iodide and dimethyl ethylenediamineare reacted for 24 hours in toluene for conversion (Patent Document 3),and (V) a method in which aniline and a sodium salt of3,3-dimethoxy-2-formyl propionitrile are reacted in the presence ofhydrochloric acid followed by converting to a substituted cyanoquinolinewith p-toluenesulfonic acid (Non-Patent Document 4).

However, these methods have the problems indicated below. In the methodof (I), in addition to requiring an extremely high reaction temperatureof 250° C., copper cyanide is used, which is highly toxic and causesproblems on disposal. In the method of (II), the total yield is onlyabout 4%, thus indicating poor productivity. In the method of (III), inaddition to using highly toxic potassium cyanide, catalytichydrogenation using an expensive palladium catalyst only demonstrates ayield of about 56%. In the method of (IV), in addition to usingtransition metals that present problems on disposal and highly toxicsodium cyanide, the reaction time is long resulting in it being not anefficient method. In the method of (V), although the method per se issuperior, the substituents on aniline are limited to strong electrondonating groups such as a methoxy group. On the other hand, the reactiondoes not proceed not only in the case of aniline substituted with afluorine atom or methyl group, but also in the case of unsubstitutedaniline, thereby indicating that this method lacks versatility.

As can be understood from the above, since conventional productionmethods using 3-cyanoquinoline derivatives as starting materials haveproblems with respect to productivity of the 3-cyanoquinoline per se aswell as only allowing the acquisition of 3-cyanoquinoline having alimited range of substituents, there has been a fervent desire for amethod for efficiently producing 3,4-dihydroisoquinoline derivatives asan alternative to these methods.

PRIOR ART DOCUMENTS Patent Documents

-   Patent Document 1: International Publication No. WO 2005/70917-   Patent Document 2: International Publication No. WO 2011/77514-   Patent Document 3: International Publication No. WO 2004/13094

Non-Patent Documents

-   Non-Patent Document 1: J. Am. Chem. Soc., Vol. 63, pp. 1553-1556    (1941)-   Non-Patent Document 2: Chem. Pharm. Bull., Vol. 26, No. 5, pp.    1558-1569 (1978)-   Non-Patent Document 3: Chem. Pharm. Bull., Vol. 26, No. 12, pp.    3856-3862 (1978)-   Non-Patent Document 4: Tetrahedron Lett., Vol. 39, pp. 4013-4016    (1998)

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

An object of the present invention is to provide an efficient method forproducing 3,4-dihydroisoquinoline derivatives and useful productionintermediates thereof.

Means for Solving the Problems

As a result of conducting extensive studies to solve the aforementionedproblems, it was found that 3,4-dihydroisoquinoline derivatives can beprepared both simply and efficiently by carrying out a reaction using anovel isoquinolinylidenemalonaldehyde derivative and aniline derivativeas starting materials to convert to a novel phenyliminopropanalderivative, followed by cyclizing in the presence of acid. Surprisingly,it became possible to provide various types of 3,4-dihydroisoquinolinederivatives since this method could be carried out in the case ofsubstituted anilines as well. What is even more surprising is that3,4-dihydroisoquinoline derivatives can be prepared at once by reactinga novel isoquinolinylidenemalonaldehyde derivative and aniline in thepresence of acid, thereby providing an effective solution to theaforementioned problems. In addition, by carrying out hydrolysis afterhaving obtained a novel isoquinolinylvinamidinium salt derivative byreacting a 1-methyl-3,4-dihydroisoquinoline derivative with Vilsmeierreagent, it was found that the isoquinolinylidenemalonaldehyde servingas raw material can be prepared efficiently, thereby leading tocompletion of the present invention.

Namely, the present invention is:

[1] a method for producing a compound represented by general formula(1):

wherein R1 and R2 independently represent an optionally substitutedalkyl group having 1 to 6 carbon atoms or R1 and R2 together with thecarbon atom to which they are bound form an optionally substitutedcycloalkyl group having 3 to 10 carbon atoms, X represents a halogenatom, optionally substituted alkyl group having 1 to 6 carbon atoms oroptionally substituted alkoxy group having 1 to 6 carbon atoms, nrepresents an integer of 0 to 4, Y represents a halogen atom, optionallysubstituted alkyl group having 1 to 6 carbon atoms or optionallysubstituted alkoxy group having 1 to 6 carbon atoms, and m represents aninteger of 0 to 4, comprising reacting a compound represented by generalformula (2):

wherein R1, R2, X, Y, n and m are the same as previously defined, in thepresence of an acid;

[2] the method for producing a compound represented by general formula(1) described in [1], wherein R1 and R2 independently represent anoptionally substituted alkyl group having 1 to 6 carbon atoms;

[3] the method for producing a compound represented by general formula(1) described in [2], wherein n is 0;

[4] the method for producing a compound represented by general formula(1) described in [1], wherein a compound represented by general formula(2) is obtained by reacting a compound represented by general formula(3):

wherein R1, R2, X and n are the same as in [1], with a compoundrepresented by general formula (4):

wherein Y and m are the same as in [1];

[5] the method for producing a compound represented by general formula(1) described in [4], wherein R1 and R2 independently represent anoptionally substituted alkyl group having 1 to 6 carbon atoms;

[6] the method for producing a compound represented by general formula(1) described in [5], wherein n is 0;

[7] the method for producing a compound represented by general formula(1) described in [4], wherein a compound represented by general formula(3) is obtained by hydrolyzing a salt containing a compound representedby general formula (5):

wherein R1, R2, X and n are the same as in [4] and R3 is an alkyl grouphaving 1 to 3 carbon atoms;

[8] the method for producing a compound represented by general formula(1) described in [7], wherein R1 and R2 independently represent anoptionally substituted alkyl group having 1 to 6 carbon atoms;

[9] the method for producing a compound represented by general formula(1) described in [8], wherein n is 0;

[10] the method for producing a compound represented by general formula(1) described in [7], wherein a salt containing a compound representedby general formula (5) is obtained by reacting a compound represented bygeneral formula (6):

wherein R1, R2, X and n are the same as in [7], with a salt containing acompound represented by general formula (7):

wherein R3 is the same as in [7] and Z represents a halogen atom;

[11] the method for producing a compound represented by general formula(1) described in [10], wherein R1 and R2 independently represent anoptionally substituted alkyl group having 1 to 6 carbon atoms;

[12] the method for producing a compound represented by general formula(1) described in [11], wherein n is 0;

[13] a method for producing a compound represented by general formula(1):

wherein R1 and R2 independently represent an optionally substitutedalkyl group having 1 to 6 carbon atoms or R1 and R2 together with thecarbon atom to which they are bound form an optionally substitutedcycloalkyl group having 3 to 10 carbon atoms, X represents a halogenatom, optionally substituted alkyl group having 1 to 6 carbon atoms oroptionally substituted alkoxy group having 1 to 6 carbon atoms, nrepresents an integer of 0 to 4, Y represents a halogen atom, optionallysubstituted alkyl group having 1 to 6 carbon atoms or optionallysubstituted alkoxy group having 1 to 6 carbon atoms, and m represents aninteger of 0 to 4, comprising reacting a compound represented by generalformula (3):

wherein R1, R2, X and n are the same as previously defined, with acompound represented by general formula (4):

wherein Y and m are the same as previously defined, in the presence ofan acid;

[14] the method for producing a compound represented by general formula(1) described in [13], wherein R1 and R2 independently represent anoptionally substituted alkyl group having 1 to 6 carbon atoms;

[15] the method for producing a compound represented by general formula(1) described in [14], wherein n is 0;

[16] the method for producing a compound represented by general formula(1) described in [13], wherein a compound represented by general formula(3) is obtained by hydrolyzing a salt containing a compound representedby general formula (5):

wherein R1, R2, X and n are the same as in [13] and R3 represents analkyl group having 1 to 3 carbon atoms;

[17] the method for producing a compound represented by general formula(1) described in [16], wherein R1 and R2 independently represent anoptionally substituted alkyl group having 1 to 6 carbon atoms;

[18] the method for producing a compound represented by general formula(1) described in [17], wherein n is 0;

[19] the method for producing a compound represented by general formula(1) described in [16], wherein a salt containing a compound representedby general formula (5) is obtained by reacting a compound represented bygeneral formula (6):

wherein R1, R2, X and n are the same as in [16], with a salt containinga compound represented by general formula (7):

wherein R3 is the same as in [16] and Z represents a halogen atom;

[20] the method for producing a compound represented by general formula(1) described in [19], wherein R1 and R2 independently represent anoptionally substituted alkyl group having 1 to 6 carbon atoms;

[21] the method for producing a compound represented by general formula(1) described in [20], wherein n is 0;

[22] a method for producing a compound represented by general formula(2), comprising reacting a compound represented by general formula (3)with a compound represented by general formula (4) to obtain a compoundrepresented by general formula (2) described in [4];

[23] the method for producing a compound represented by general formula(2) described in [22], wherein R1 and R2 independently represent anoptionally substituted alkyl group having 1 to 6 carbon atoms;

[24] the method for producing a compound represented by general formula(2) described in [23], wherein n is 0;

[25] a method for producing a compound represented by general formula(3), comprising hydrolyzing a salt containing a compound represented bygeneral formula (5) to obtain a compound represented by general formula(3) described in [7];

[26] the method for producing a compound represented by general formula(3) described in [25], wherein R1 and R2 independently represent anoptionally substituted alkyl group having 1 to 6 carbon atoms;

[27] the method for producing a compound represented by general formula(3) described in [26], wherein n is 0;

[28] a method for producing a salt containing a compound represented bygeneral formula (5), comprising reacting a compound represented bygeneral formula (6) with a salt containing a compound represented bygeneral formula (7) to obtain a salt containing a compound representedby general formula (5) described in [10];

[29] the method for producing a salt containing a compound representedby general formula (5) described in [28], wherein R1 and R2independently represent an optionally substituted alkyl group having 1to 6 carbon atoms;

[30] the method for producing a salt containing a compound representedby general formula (5) described in [29], wherein n is 0;

[31] a compound represented by general formula (2) described in [1];

[32] the compound represented by general formula (2) described in [31],wherein R1 and R2 independently represent an optionally substitutedalkyl group having 1 to 6 carbon atoms;

[33] the compound represented by general formula (2) described in [32],wherein n is 0;

[34] a compound represented by general formula (3) described in [4];

[35] the compound represented by general formula (3) described in [34],wherein R1 and R2 independently represent an optionally substitutedalkyl group having 1 to 6 carbon atoms;

[36] the compound represented by general formula (3) described in [35],wherein n is 0;

[37] a salt containing a compound represented by general formula (5)described in [7];

[38] the salt containing a compound represented by general formula (5)described in [37], wherein R1 and R2 independently represent anoptionally substituted alkyl group having 1 to 6 carbon atoms; and,

[39] the salt containing a compound represented by general formula (5)described in [38], wherein n is 0.

Effects of the Invention

According to the present invention, a novel and efficient method forproducing 3,4-dihydroisoquinoline derivatives and useful novelproduction intermediates thereof can be provided. In addition, since agroup of target compounds can be prepared efficiently by simpleoperation, the method of the present invention is also suitable as anindustrial manufacturing method.

MODE FOR CARRYING OUT THE INVENTION

The following provides a detailed explanation of embodiments forcarrying out the present invention.

An explanation is first provided of compounds represented by generalformula (1).

In general formula (1), R1 and R2 are independent and may be the same ordifferent.

The substituents of the optionally substituted alkyl group having 1 to 6carbon atoms at R1 and R2 in general formula (1) refer to halogen atomsand alkoxy groups having 1 to 6 carbon atoms. The halogen atom isfluorine, chlorine, bromine or iodine. The alkoxy group having 1 to 6carbon atoms represents a linear or branched alkoxy group such as amethoxy group, ethoxy group, propoxy group, isopropoxy group, butyloxygroup, isobutyloxy group, s-butyloxy group, t-butyloxy group, pentoxygroup, isopentoxy group, 2-methylbutyloxy group, neopentoxy group,1-ethylpropoxy group, hexyloxy group, 4-methylpentoxy group,3-methylpentoxy group, 2-methylpentoxy group, 1-methylpentoxy group,3,3-dimethylbutyloxy group, 2,2-dimethylbutyloxy group,1,1-dimethylbutyloxy group, 1,2-dimethylbutyloxy group,1,3-dimethylbutyloxy group, 2,3-dimethylbutyloxy group or2-ethylbutyloxy group. It is preferably an alkoxy group having 1 to 4carbon atoms and more preferably a methoxy group, ethoxy group, propoxygroup or isopropoxy group. There are no particular limitations on thenumber of substituents and each substituent may be the same ordifferent.

The alkyl group in the optionally substituted alkyl group having 1 to 6carbon atoms at R1 and R2 in general formula (1) represents a linear orbranched alkyl group such as a methyl group, ethyl group, propyl group,isopropyl group, butyl group, isobutyl group, s-butyl group, t-butylgroup, pentyl group, isopentyl group, 2-methylbutyl group, neopentylgroup, 1-ethylpropyl group, hexyl group, 4-methylpentyl group,3-methylpentyl group, 2-methylpentyl group, 1-methylpentyl group,3,3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutylgroup, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group,2,3-dimethylbutyl group or 2-ethylbutyl group. It is preferably an alkylgroup having 1 to 3 carbon atoms and more preferably a methyl group orethyl group.

The substituents of the optionally substituted cycloalkyl group having 3to 10 carbon atoms formed by R1 and R2 together with the carbon atom towhich they are bound in general formula (1) have the same meaning as thesubstituents of the optionally substituted alkyl group having 1 to 6carbon atoms at R1 and R2 in general formula (1). There are noparticular limitations on the number of substituents and eachsubstituent may be the same or different.

The cycloalkyl group in the optionally substituted cycloalkyl grouphaving 3 to 10 carbon atoms formed by R1 and R2 together with the carbonatom to which they are bound in general formula (1) refers to amonocyclic or polycyclic cycloalkyl group having 3 to 10 carbon atomssuch as a cyclobutyl group, cyclopentyl group, cyclohexyl group,cycloheptyl group or norbornyl group. It is preferably a cyclobutylgroup, cyclopentyl group, cyclohexyl group or cycloheptyl group, andmore preferably a cyclopentyl group.

The halogen atom at X in general formula (1) refers to fluorine,chlorine, bromine or iodine.

The optionally substituted alkyl group having 1 to 6 carbon atoms at Xin general formula (1) has the same meaning as the optionallysubstituted alkyl group having 1 to 6 carbon atoms at R1 and R2 ingeneral formula (1).

The substituents of the optionally substituted alkoxy group having 1 to6 carbon atoms at X in general formula (1) refer to a halogen atom, thatis, fluorine, chlorine, bromine or iodine. There are no particularlimitations on the number of substituents and each substituent may bethe same or different.

The alkoxy group of the optionally substituted alkoxy group having 1 to6 carbon atoms at X in general formula (1) refers to a linear orbranched alkoxy group such as a methoxy group, ethoxy group, propoxygroup, isopropoxy group, butyloxy group, isobutyloxy group, s-butyloxygroup, t-butyloxy group, pentoxy group, isopentoxy group,2-methylbutyloxy group, neopentoxy group, 1-ethylpropoxy group, hexyloxygroup, 4-methylpentoxy group, 3-methylpentoxy group, 2-methylpentoxygroup, 1-methylpentoxy group, 3,3-dimethylbutyloxy group,2,2-dimethylbutyloxy group, 1,1-dimethylbutyloxy group,1,2-dimethylbutyloxy group, 1,3-dimethylbutyloxy group,2,3-dimethylbutyloxy group or 2-ethylbutyloxy group. It is preferably analkoxy group having 1 to 4 carbon atoms and more preferably a methoxygroup, ethoxy group, propoxy group or isopropoxy group.

n in general formula (1) is an integer of 0 to 4.

X may be the same or different when n in general formula (1) is 2 ormore.

The halogen atom at Y in general formula (1) has the same meaning as thehalogen atom at X in general formula (1).

The optionally substituted alkyl group having 1 to 6 carbon atoms at Yin general formula (1) has the same meaning as the optionallysubstituted alkyl group having 1 to 6 carbon atoms at X in generalformula (1).

The optionally substituted alkoxy group having 1 to 6 carbon atoms at Yin general formula (1) has the same meaning as the optionallysubstituted alkoxy group having 1 to 6 carbon atoms at X in generalformula (1).

m in general formula (1) is an integer of 0 to 4.

Y may be the same or different when m in general formula (1) is 2 ormore.

R1, R2, X, Y, n and m in general formula (2) have the same meanings asin general formula (1).

A compound represented by general formula (2) includes the isomersindicated below. These isomers may be present alone or a mixture of twoor more types. There are no particular limitations on the mixing ratioin the case of the mixtures.

The following provides an explanation of a method for converting from acompound represented by general formula (2) to a compound represented bygeneral formula (1) in the presence of an acid.

The acid used can be an inorganic acid or organic acid, and there are noparticular limitations thereon provided it allows the target reaction toproceed. Examples of the inorganic acids include hydrochloric acid,sulfuric acid and phosphoric acid, and the inorganic acid is preferablysulfuric acid or phosphoric acid. Examples of the organic acids includeorganic carboxylic acids and organic sulfonic acids. Examples of theorganic carboxylic acids include trifluoroacetic acid and the like.Examples of the organic sulfonic acids include methanesulfonic acid,trifluoromethanesulfonic acid, benzenesulfonic acid, toluenesulfonicacid, xylenesulfonic acid, chlorobenzenesulfonic acid andnaphthalenesulfonic acid. In the case the sulfonic acid has theregioisomers, any isomer is effective.

There are no particular limitations on the amount of acid used providedit is more than 1 equivalent. It is preferably 1 equivalent to 3equivalents.

Although there are no particular limitations on solvent used in thereaction provided it allows the reaction to proceed, examples thereofinclude benzene-based solvents such as benzene, toluene, xylene,mesitylene, chlorobenzene or dichlorobenzene, ester-based solvents suchas ethyl acetate, isopropyl acetate or butyl acetate, nitrile-basedsolvents such as acetonitrile, amide-based solvents such asN-methylpyrrolidone, N,N-dimethylformamide or N,N-dimethylacetamide,urea-based solvents such as 1,3-dimethyl-2-imidazolidinone, andchlorine-based solvents such as dichloroethane or chloroform. It ispreferably a benzene-based solvent. One type of solvent may be usedalone or two or more types can be mixed at an arbitrary ratio.

Although there are no particular limitations on the amount of solventused provided it allows the reaction to proceed, it is normally 3 timesto 50 times the weight of the compound represented by general formula(2).

Although there are no particular limitations on the reaction temperatureprovided it allows the reaction to proceed, it is normally higher than40° C. and lower than 200° C. or the boiling point of the solvent.

With respect to moisture present in the reaction, the reaction proceedsefficiently by removing water from the reaction system. At this time,there are no particular limitations on the use of normal pressure orreduced pressure provided the reaction is allowed to proceed. Thepressure may be suitably set as necessary.

The following provides a description of a method for post-treatment ofthe reaction.

A compound represented by general formula (1) forms a salt with acidfollowing completion of the reaction. With regard to the form of thesalt, there is one pair of acid or two pairs of acid, or a mixture ofone pair and two pairs of acids based on the compound represented bygeneral formula (1). There are no particular limitations on the mixingratio in the case of the mixtures.

In the case a salt of the compound represented by general formula (1)precipitates, a target substance can be obtained by filtration. Inaddition, when carrying out a filtration procedure, a solvent can alsobe added to the reaction mixture. Examples of the solvents used include,but are not limited to, water, ether-based solvents such as diethylether, diisopropyl ether or methyl t-butyl ether, alcohol-based solventssuch as methanol, ethanol or isopropanol, benzene-based solvents such asbenzene, toluene, xylene, mesitylene, chlorobenzene or dichlorobenzene,ester-based solvents such as ethyl acetate, isopropyl acetate or butylacetate, nitrile-based solvents such as acetonitrile, hydrocarbon-basedsolvents such as hexane, heptane, cyclohexane or methylcyclohexane, andhalogen-based solvents such as dichloromethane, dichloroethane orchloroform.

The salt of a compound represented by general formula (1) obtained inthis manner can be subjected to washing, re-precipitation orrecrystallization with a suitable solvent as necessary. Although thereare no particular limitations on the solvent used provided it allows thetarget procedure to be carried out, examples thereof include water,ether-based solvents such as diethyl ether, diisopropyl ether or methylt-butyl ether, alcohol-based solvents such as methanol, ethanol orisopropanol, benzene-based solvents such as benzene, toluene, xylene,mesitylene, chlorobenzene or dichlorobenzene, ester-based solvents suchas ethyl acetate, isopropyl acetate or butyl acetate, nitrile-basedsolvents such as acetonitrile, hydrocarbon-based solvents such ashexane, heptane, cyclohexane or methylcyclohexane, and halogen-basedsolvents such as dichloromethane, dichloroethane or chloroform. Inaddition, one type of these solvents can be used alone or two or moretypes can be used by mixing at an arbitrary ratio.

The salt of a compound represented by general formula (1) can also beconverted to a free compound represented by general formula (1) with anaqueous alkaline solution. The aqueous alkaline solution used is that inwhich, for example, sodium hydroxide, potassium hydroxide, sodiumbicarbonate, potassium bicarbonate, sodium carbonate, potassiumcarbonate or ammonia or the like, is dissolved in water. At this time, asolvent can be added, examples of which include water, ether-basedsolvents such as diethyl ether, diisopropyl ether or methyl t-butylether, alcohol-based solvents such as methanol, ethanol or isopropanol,benzene-based solvents such as benzene, toluene, xylene, mesitylene,chlorobenzene or dichlorobenzene, ester-based solvents such as ethylacetate, isopropyl acetate or butyl acetate, hydrocarbon-based solventssuch as hexane, heptane, cyclohexane or methylcyclohexane, andhalogen-based solvents such as dichloromethane, dichloroethane orchloroform. One type of these solvents can be used alone or two or moretypes can be used by mixing at an arbitrary ratio. In addition, if astate after desalting allows liquid separation, liquid separation can bedirectly carried out. There are no particular limitations on the numberof liquid separation procedures. The target compound represented bygeneral formula (1) can be obtained by distilling off the solventfollowing liquid separation. Although moisture can be removed with adesiccant such as sodium sulfate or magnesium sulfate before distillingoff the solvent, this operation is not essential. In addition, a freecompound represented by general formula (1) can be filtered out in thecase the compound precipitates.

The free compound represented by general formula (1) obtained in thismanner can be further purified by washing, re-precipitating orrecrystallizing with a suitable solvent. Examples of the solvents usedinclude water, ether-based solvents such as diethyl ether, diisopropylether or methyl t-butyl ether, alcohol-based solvents such as methanol,ethanol or isopropanol, benzene-based solvents such as benzene, toluene,xylene, mesitylene, chlorobenzene or dichlorobenzene, ester-basedsolvents such as ethyl acetate, isopropyl acetate or butyl acetate,hydrocarbon-based solvents such as hexane, heptane, cyclohexane ormethylcyclohexane, and halogen-based solvents such as dichloromethane,dichloroethane or chloroform, and one type of these solvents can be usedalone or two or more types can be used by mixing at an arbitrary ratio.In addition, the compound can also be purified by column chromatography.The purification procedure can be suitably set according to the targetpurity.

In addition, a liquid separation procedure can be carried out followingcompletion of the reaction by adding an aqueous alkaline solutionirrespective of the precipitated state of the compound represented bygeneral formula (1). The aqueous alkaline solution used is that inwhich, for example, sodium hydroxide, potassium hydroxide, sodiumbicarbonate, potassium bicarbonate, sodium carbonate, potassiumcarbonate or the like, is dissolved in water. A suitable solvent can beadded to facilitate the liquid separation procedure. Examples of theadded solvent include ether-based solvents such as diethyl ether,diisopropyl ether or methyl t-butyl ether, benzene-based solvents suchas benzene, toluene, xylene, mesitylene, chlorobenzene ordichlorobenzene, ester-based solvents such as ethyl acetate, isopropylacetate or butyl acetate, hydrocarbon-based solvents such as hexane,heptane, cyclohexane or methylcyclohexane, and halogen-based solventssuch as dichloromethane, dichloroethane or chloroform. The solutioncontaining a compound represented by general formula (1) obtained inthis manner can be repeatedly subjected to a liquid separation procedureusing the aforementioned aqueous alkaline solution or water asnecessary.

In the case of a solution in which a compound represented by generalformula (1) has been extracted, the target compound represented bygeneral formula (1) can be obtained by distilling off the solvent.Although moisture can be removed with a desiccant such as sodium sulfateor magnesium sulfate before distilling off the solvent, this operationis not essential. The compound represented by general formula (1)obtained in this manner can be purified by washing, re-precipitating orrecrystallizing or by column chromatography with a suitable solvent, inthe same manner as the previously described methods.

The following provides an explanation of a method for obtaining acompound represented by general formula (2) by reacting a compoundrepresented by general formula (3) with a compound represented bygeneral formula (4).

R1, R2, X and n in general formula (3) have the same meanings as R1, R2,X and n in general formula (1).

The compound represented by general formula (3) includes the isomersindicated below. These isomers may be present alone or a mixture of twoor more types. There are no particular limitations on the mixing ratioin the case of the mixtures.

Y and m in general formula (4) have the same meanings as Y and m ingeneral formula (1).

The compounds represented by general formula (4) can be acquired ascommercial products.

There are no particular limitations on the amount of the compoundrepresented by general formula (4) used in the reaction provided it ismore than 1 equivalent based on a compound represented by generalformula (3) and allows the target reaction to proceed. The amount usedis preferably 1 equivalent to 3 equivalents.

Although a solvent can be used in the reaction, the use of a solvent isnot necessarily required.

Although there are no particular limitations on the solvent used in thereaction provided it allows the reaction to proceed, examples thereofinclude ether-based solvents such as diethyl ether, diisopropyl ether ormethyl t-butyl ether, alcohol-based solvents such as methanol, ethanolor isopropanol, benzene-based solvents such as benzene, toluene, xylene,mesitylene, chlorobenzene or dichlorobenzene, ester-based solvents suchas ethyl acetate, isopropyl acetate or butyl acetate, nitrile-basedsolvents such as acetonitrile, amide-based solvents such asN-methylpyrrolidone, N,N-dimethylformamide or N,N-dimethylacetamide,urea-based solvents such as 1,3-dimethyl-2-imidazolidinone, andchlorine-based solvents such as dichloromethane, dichloroethane orchloroform. The solvent is preferably a benzene-based solvent.

Although there are no particular limitations on the amount of solventused in the reaction provided it allows the reaction to proceed, it isnormally 3 times to 50 times the weight of the compound represented bygeneral formula (3).

Although there are no particular limitations on the temperature whencarrying out the reaction provided it allows the reaction to proceed, itis normally higher than 40° C. and lower than 150° C. or the boilingpoint of the solvent.

With respect to moisture present in the reaction, the reaction proceedsefficiently by removing water from the reaction system. At this time,there are no particular limitations on the use of normal pressure orreduced pressure provided the reaction is allowed to proceed. Thepressure may be suitably set as necessary.

The following provides a description of a method for post-treatment ofthe reaction.

In the case a compound represented by general formula (2) precipitatesfollowing completion of the reaction, the compound can be filtered outand isolated while in the form of a precipitate. In addition, thecompound can also be used directly in the next step without isolating.Moreover, the compound can be used in the next step after havingdistilled off the solvent.

Although the compound represented by general formula (2) formedfollowing completion of the reaction can be subjected to a liquidseparation procedure provided the compound does not decompose, a liquidseparation procedure is not essential.

The resulting compound represented by general formula (2) can be washed,re-precipitated or recrystallized with a suitable solvent. Examples ofsolvents used include water, ether-based solvents such as diethyl ether,diisopropyl ether or methyl t-butyl ether, alcohol-based solvents suchas methanol, ethanol or isopropanol, benzene-based solvents such asbenzene, toluene, xylene, mesitylene, chlorobenzene or dichlorobenzene,ester-based solvents such as ethyl acetate, isopropyl acetate or butylacetate, hydrocarbon-based solvents such as hexane, heptane, cyclohexaneor methylcyclohexane, and halogen-based solvents such asdichloromethane, dichloroethane or chloroform, and one type can be usedalone or two or more types can be used by mixing at an arbitrary ratio.In addition, the compound can also be purified by column chromatography.Purification can be suitably set according to the target purity.

The compound represented by general formula (2) obtained in this mannercan be converted to a compound represented by general formula (1) by amethod in which it is allowed to react in the presence of an acid aspreviously described.

The following provides an explanation of a method for obtaining acompound represented by general formula (3) by hydrolyzing a saltcontaining a compound represented by general formula (5).

R1, R2, X and n in general formula (5) have the same meanings as R1, R2,X and n in general formula (1).

The alkyl group having 1 to 3 carbon atoms at R3 in general formula (5)refers to a methyl group, ethyl group, propyl group or isopropyl group,and is preferably a methyl group.

Examples of the salts containing a compound represented by generalformula (5) include salts of a compound represented by general formula(5) with an anion, such as chloride ion, bromide ion, iodide ion,dichlorophosphate ion, perchlorate ion or hexafluorophosphate ion. Thereare no particular limitations on the type of anion provided it allowsthe reaction to proceed.

The compound represented by general formula (5) includes the isomersindicated below. These isomers may be present alone or a mixture of twoor more types. There are no particular limitations on the mixing ratioin the case of the mixtures.

Water is required when carrying out the reaction. In addition, thereaction can be carried out using water as solvent.

There are no particular limitations on the amount of water used providedit is more than 2 equivalents based on the compound represented bygeneral formula (5). Water is normally used in excess, and the amountused is 2 to 50 times the weight of the compound represented by generalformula (5).

The pH is preferably from neutral to alkaline when carrying out thereaction. When making the pH alkaline, an inorganic base such as sodiumhydroxide, potassium hydroxide, sodium bicarbonate, potassiumbicarbonate, sodium carbonate or potassium carbonate can be used. Theuse amount thereof is suitably set so that the aqueous layer isalkaline.

A solvent can be used when carrying out the reaction. Examples of thesolvents used include ether-based solvents such as diethyl ether,diisopropyl ether or methyl t-butyl ether, alcohol-based solvents suchas methanol, ethanol or isopropanol, benzene-based solvents such asbenzene, toluene, xylene, mesitylene, chlorobenzene or dichlorobenzene,ester-based solvents such as ethyl acetate, isopropyl acetate or butylacetate, hydrocarbon-based solvents such as hexane, heptane, cyclohexaneor methylcyclohexane, and halogen-based solvents such asdichloromethane, dichloroethane or chloroform. One type of thesesolvents can be used alone or two or more types can be used by mixing atan arbitrary ratio. Although there are no limitations on the reactionstate provided it allows the reaction to proceed, the reaction state maybe a single layer or two layers separated.

The amount of the solvent used is normally 2 times to 50 times theweight of the salt containing a compound represented by general formula(5).

The reaction temperature is normally higher than −10° C. and lower than150° C. or the boiling point of the solvent. The reaction temperature ispreferably higher than 20° C. and lower than 120° C. or the boilingpoint of the solvent.

The reaction can be made to proceed efficiently by removing dialkylamine((R3)₂NH) formed during the reaction from the reaction system.

The pressure when carrying out the reaction may be normal pressure orthe reaction can be carried out under reduced pressure so as toefficiently remove dialkylamine.

The following provides a description of a method for post-treatment ofthe reaction.

Following completion of the reaction, a liquid separation procedure canbe carried out if the organic layer and aqueous layer are in a separatedstate. A solvent can also be added at this time. Examples of the addedsolvent include ether-based solvents such as diethyl ether, diisopropylether or methyl t-butyl ether, benzene-based solvents such as benzene,toluene, xylene, mesitylene, chlorobenzene or dichlorobenzene,ester-based solvents such as ethyl acetate, isopropyl acetate or butylacetate, hydrocarbon-based solvents such as hexane, heptane, cyclohexaneor methylcyclohexane, and halogen-based solvents such asdichloromethane, dichloroethane or chloroform. In addition, a liquidseparation procedure can be carried out using the aforementioned addedsolvents even when the reaction is carried out with water alone. Onetype of solvent can be used alone or two or more types can be used bymixing at an arbitrary ratio. In addition, the liquid separationprocedure can be repeated corresponding to the target purity.

The compound represented by general formula (3) present in a solventobtained in this manner can be used as is without subjecting topurification, or can be used after having distilled off the solvent.Although moisture can be removed with a desiccant such as sodium sulfateor magnesium sulfate before distilling off the solvent, this operationis not essential. In addition, the compound can also be purified bywashing, re-precipitating or recrystallizing using a suitable solvent ifnecessary. Examples of the solvents used include water, ether-basedsolvents such as diethyl ether, diisopropyl ether or methyl t-butylether, alcohol-based solvents such as methanol, ethanol or isopropanol,benzene-based solvents such as benzene, toluene, xylene, mesitylene,chlorobenzene or dichlorobenzene, ester-based solvents such as ethylacetate, isopropyl acetate or butyl acetate, hydrocarbon-based solventssuch as hexane, heptane, cyclohexane or methylcyclohexane, andhalogen-based solvents such as dichloromethane, dichloroethane orchloroform, and one type of these solvents can be used alone or two ormore types can be used by mixing at an arbitrary ratio. In addition, thecompound can also be purified by column chromatography. Purification issuitably set according to the target purity.

The compound represented by general formula (3) obtained in the mannerdescribed above can be converted to a compound represented by generalformula (1) by reacting with the aforementioned compound represented bygeneral formula (4) to obtain a compound represented by general formula(2) and further reacting under acidic conditions.

The following provides an explanation of a method for producing a saltcontaining a compound represented by general formula (5) that comprisesreacting a compound represented by general formula (6) with a saltcontaining a compound represented by general formula (7) to obtain asalt containing a compound represented by general formula (5).

R1, R2, X and n in general formula (6) have the same meanings as R1, R2,X and n in general formula (1).

The compound represented by general formula (6) can be prepared withreference to, for example, International Publication No. WO 2003/64389or International Publication No. WO 2001/16275.

R3 in general formula (7) has the same meaning as R3 in general formula(5).

The compound represented by general formula (7) can be prepared from aformamide derivative such as N,N-dimethylformamide and a halogenatingagent.

Examples of the halogenating agents used include, but are not limitedto, oxalyl chloride, phosgene, phosphorous oxychloride and thionylchloride.

The salt containing a compound represented by general formula (7)includes salts of a compound represented by general formula (7) with ananion derived from the halogenating agent. Examples of the anionsderived from the halogenating agent include anions such as chloride ionand dichlorophosphate ion.

The amount of a compound represented by general formula (7) used is morethan 2 equivalents based on a compound represented by general formula(6), and is preferably 2 equivalents to 5 equivalents.

A solvent can be used in the reaction. Specific examples of the solventsinclude benzene-based solvents such as benzene, toluene, xylene,mesitylene, chlorobenzene or dichlorobenzene, ester-based solvents suchas ethyl acetate, isopropyl acetate or butyl acetate, nitrile-basedsolvents such as acetonitrile, amide-based solvents such asN-methylpyrrolidone, N,N-dimethylformamide or N,N-dimethylacetamide,urea-based solvents such as 1,3-dimethyl-2-imidazolidinone, andchlorine-based solvents such as dichloromethane, dichloroethane orchloroform, and one type of these solvents can be used alone or two ormore types can be used by mixing at an arbitrary ratio.

Although there are no particular limitations on the amount of solventused provided it allows the reaction to proceed, it is normally 3 timesto 50 times the weight of the compound represented by general formula(6).

Although there are no particular limitations on the reaction temperatureprovided it allows the reaction to proceed, it is higher than −10° C.and lower than 150° C. or the boiling point of the solvent, and ispreferably higher than 20° C. and lower than 120° C. or the boilingpoint of the solvent.

Examples of the reaction method include a procedure in which a compoundrepresented by general formula (7) is prepared from a formamidederivative and a halogenating agent, followed by reacting with acompound represented by general formula (6), and a procedure in which ahalogenating agent is allowed to react with a mixture of a compoundrepresented by general formula (6) and a formamide derivative. There areno particular limitations on the method used provided it allows thetarget reaction to proceed, and the method can be set as is suitable.

The following provides a description of a method for post-treatment ofthe reaction.

Water can be added following completion of the reaction. A compoundrepresented by general formula (5) is present in the aqueous layer inthe case of having added a neutral or acidic aqueous solution.Alternatively, conversion to a compound represented by general formula(3) may occur in the case of having added an alkaline aqueous solution.

In the case the aqueous layer is acidic after having added water, theliquid can be separated with a solvent that is incompatible with water.Examples of the solvents used include ether-based solvents such asdiethyl ether, diisopropyl ether or methyl t-butyl ether, benzene-basedsolvents such as benzene, toluene, xylene, mesitylene, chlorobenzene ordichlorobenzene, ester-based solvents such as ethyl acetate, isopropylacetate or butyl acetate, hydrocarbon-based solvents such as hexane,heptane, cyclohexane or methylcyclohexane, and halogen-based solventssuch as dichloromethane, dichloroethane or chloroform. A liquidseparation procedure is not essential, and the reaction liquid can betransferred to the next step while still in the state of two layers.

In the case a salt of a compound represented by general formula (5)precipitates following completion of the reaction, it can be isolated byfiltration. In addition, after having distilled off the solvent, it mayalso be isolated by adding a solvent that causes the salt toprecipitate. Removal of the solvent by distillation is not essential atthis time, but rather is suitably assessed based on the state of thereaction mixture. Examples of the solvents used include ether-basedsolvents such as diethyl ether, diisopropyl ether or methyl t-butylether, benzene-based solvents such as benzene, toluene, xylene,mesitylene, chlorobenzene or dichlorobenzene, ester-based solvents suchas ethyl acetate, isopropyl acetate or butyl acetate, nitrile-basedsolvents such as acetonitrile, hydrocarbon-based solvents such ashexane, heptane, cyclohexane or methylcyclohexane, and halogen-basedsolvents such as dichloromethane, dichloroethane or chloroform.

The salt of a compound represented by general formula (5) can also beisolated by salt exchange with perchlorate ion or perfluorophosphate ionor the like.

In addition, the reaction of the next step can be carried out directlyfollowing completion of the reaction. In addition, it can be transferredto the next step after only carrying out removal of solvent bydistillation.

The salt containing a compound represented by general formula (5)obtained in this manner can be converted to a compound represented bygeneral formula (1) by converting to a compound represented by generalformula (3) through the aforementioned hydrolysis, followed by reactingwith a compound represented by general formula (4) to obtain a compoundrepresented by general formula (2) and further reacting under acidicconditions.

The following provides a description of a method in which a compoundrepresented by general formula (3) and a compound represented by generalformula (4) are reacted in the presence of an acid to convert to acompound represented by general formula (1).

As was previously described, after obtaining a compound represented bygeneral formula (2) by reacting a compound represented by generalformula (3) with a compound represented by general formula (4), thecompound represented by general formula (2) can be converted to acompound represented by general formula (1) by adding an acid.Surprisingly, by reacting with a compound represented by general formula(4) in the presence of acid in advance, a compound represented bygeneral formula (3) can also be converted to a compound represented bygeneral formula (1).

There are no particular limitations on the amount of the compoundrepresented by general formula (4) used in the reaction provided it ismore than 1 equivalent based on the compound represented by generalformula (3) and allows the reaction to proceed. The amount used ispreferably 1 equivalent to 3 equivalents, and more preferably 1equivalent to 1.5 equivalents.

The acid used can be an inorganic acid or organic acid, and there are noparticular limitations thereon provided the target reaction is allowedto proceed. Examples of the inorganic acids include hydrochloric acid,sulfuric acid and phosphoric acid, and the inorganic acid is preferablysulfuric acid or phosphoric acid. Examples of the organic acids includeorganic carboxylic acids and organic sulfonic acids. Examples of theorganic carboxylic acids include trifluoroacetic acid and the like.Examples of the organic sulfonic acids include methanesulfonic acid,trifluoromethanesulfonic acid, benzenesulfonic acid, toluenesulfonicacid, xylenesulfonic acid, chlorobenzenesulfonic acid andnaphthalenesulfonic acid. In the case the sulfonic acid has theregioisomers, any isomer is effective.

There are no particular limitations on the amount of acid used providedit is more than 1 equivalent. The amount of acid used is preferably 1equivalent to 3 equivalents.

There are no particular limitations on the method used to chargereagents provided it allows the reaction to proceed, and it may be amethod in which acid is mixed with a compound represented by generalformula (4) followed by adding a compound represented by general formula(3), or a method in which a compound represented by general formula (3),a compound represented by general formula (4) and acid are mixed all atonce.

Although there are no particular limitations on the solvent used in thereaction provided it allows the reaction to proceed, examples thereofinclude benzene-based solvents such as benzene, toluene, xylene,mesitylene, chlorobenzene or dichlorobenzene, ester-based solvents suchas ethyl acetate, isopropyl acetate or butyl acetate, nitrile-basedsolvents such as acetonitrile, amide-based solvents such asN-methylpyrrolidone or N,N-dimethylformamide, urea-based solvents suchas 1,3-dimethyl-2-imidazolidinone, and chlorine-based solvents such asdichloroethane or chloroform. The solvent is preferably a benzene-basedsolvent. One type of solvent can be used alone or two or more types canbe used by mixing at an arbitrary ratio.

Although there are no particular limitations on the amount of solventused in the reaction provided it allows the reaction to proceed, it isnormally 3 to 50 times the weight of the compound represented by generalformula (3).

Although there are no particular limitations on the reaction temperatureprovided it allows the reaction to proceed, it is normally higher than40° C. and lower than 200° C. or the boiling point of the solvent.

With respect to moisture present in the reaction, the reaction proceedsefficiently by removing water from the reaction system. At this time,there are no particular limitations on the use of normal pressure orreduced pressure provided the reaction is allowed to proceed. It may besuitably set as necessary.

With respect to post-treatment following the reaction, it can be carriedout using the same procedures as the methods for post-treatmentexplained in the method for converting a salt containing a compoundrepresented by general formula (2) to a compound represented by generalformula (1) in the presence of acid.

The compound represented by general formula (3) obtained by hydrolyzinga salt containing a compound represented by general formula (5) aspreviously described can be further converted to a compound representedby general formula (1) by reacting with a compound represented bygeneral formula (4) in the presence of an acid.

The salt containing a compound represented by general formula (5)obtained by reacting a compound represented by general formula (6) witha salt containing a compound represented by general formula (7) aspreviously described can be converted to a compound represented bygeneral formula (1) by hydrolyzing to convert to a compound representedby general formula (3), followed by further reacting with a compoundrepresented by general formula (4) in the presence of an acid.

The method for producing a compound represented by general formula (2)by reacting a compound represented by general formula (3) with acompound represented by general formula (4) is a novel reaction, and theresulting compound represented by general formula (2) is also a novelcompound. On the basis of the above, this novel reaction and this novelcompound can be understood to be useful in the present invention.

The method for producing a compound represented by general formula (3)by hydrolyzing a salt containing a compound represented by generalformula (5) is a novel reaction, and the resulting compound representedby general formula (3) is also a novel compound. On the basis of theabove, this novel reaction and this novel compound can be understood tobe useful in the present invention.

The method for producing a salt containing a compound represented bygeneral formula (5) by reacting a compound represented by generalformula (6) with a salt containing a compound represented by generalformula (7) is novel, and the resulting salt containing a compoundrepresented by general formula (5) is also a novel compound. On thebasis of the above, this novel reaction and this novel compound can beunderstood to be useful in the present invention.

According to the present invention as described above, a simple andefficient method for producing 3,4-dihydroisoquinoline derivativesrepresented by general formula (1), and useful, novel productionintermediates thereof, can be provided.

EXAMPLES

Although the following provides a more detailed explanation of thepresent invention by indicating examples thereof, the present inventionis not limited thereto.

-   N,N-dimethylformamide is referred to as DMF,    1,3,3-trimethyl-3,4-dihydroisoquinoline is referred to as Compound    (I),-   N-(2-(3,3-dimethyl-3,4-dihydroisoquinolin-1-yl)-3-(dimethylamino)allylidene)-N-methylmethanaminium    chloride is referred to as Compound (II),-   2-(3,3-dimethyl-3,4-dihydroisoquinolin-1(2H)-ylidene)malonaldehyde    is referred to as Compound (III),-   2-(3,3-dimethyl-3,4-dihydroisoquinolin-1(2H)-ylidene)-3-(phenylimino)propanal    is referred to as Compound (IV),    3-(3,3-dimethyl-3,4-dihydroisoquinolin-1-yl) quinoline is referred    to as Compound (V), p-toluenesulfonic acid is referred to as TsOH,    m-xylenesulfonic acid is referred to as m-XySO₃H, and    high-performance liquid chromatography is referred to as HPLC.

Example 1 Synthesis of Compound (III)—Part 1

180 ml of xylene charged with 12.66 g of DMF were cooled to 4° C.followed by carefully dropping 21.98 g of oxalyl chloride at 10° C. orlower over the course of 20 minutes. After stirring for 30 minutes atroom temperature (26° C.), 20 ml of xylene containing 10.00 g ofCompound (I) were dropped in over the course of 10 minutes. Next, thetemperature was raised to 80° C. followed by stirring for 2 hours at thesame temperature. After cooling to room temperature (26° C.), adding 100ml of water and stirring well, a xylene layer and aqueous layer wereseparated to obtain the aqueous layer containing Compound (II).

The resulting aqueous layer containing Compound (II) was dropped into32.3 g of 30% sodium hydroxide and allowed to react for 2 hours at 95°C. After cooling to 8° C., 45.76 g of concentrated hydrochloric acidwere dropped in at 30° C. or lower (pH≈3.5). After stifling for 1 hour,the precipitate was filtered out to obtain 10.65 g of Compound (II) as alight brown solid.

Material Data of Compound (III):

¹H-NMR (CDCl₃) δ: 12.12 (1H, br s), 9.79 (2H, s), 7.64 (1H, d, J=7.6Hz), 7.55 (1H, t, J=7.6 Hz), 7.38 (1H, t, J=7.6 Hz), 7.29 (1H, d, J=7.6Hz), 2.91 (2H, s), 1.32 (6H, s).

Example 2 Synthesis of Compound (IV)

100 ml of toluene charged with 10.00 g of Compound (III) and 4.06 g ofaniline were allowed to react for 10 hours while refluxing and removingwater. 2.03 g of aniline were additionally added and allowed to reactfor 4 hours while refluxing and removing water. After cooling to roomtemperature, diethyl ether was added and the precipitate was filteredout. 9.41 g of Compound (IV) were obtained as a yellow solid. Yield:71%.

Material Data of Compound (IV):

¹H-NMR (CDCl₃) δ: 13.35 (1H, br s), 9.70 (1H, s), 9.02 (1H, br s), 7.60(1H, d, J=7.6 Hz), 7.50-7.48 (1H, m), 7.38-7.36 (3H, m), 7.29-7.28 (1H,m), 7.21-7.18 (3H, m), 2.89 (2H, s), 1.32 (6H, s).

Example 3 Synthesis of Compound (V) Using Compound (IV) asSubstrate—Part 1

5 ml of xylene charged with 120 mg of Compound (IV) and 74 mg ofp-toluenesulfonic acid monohydrate were allowed to react for 3 hourswhile refluxing. Following completion of the reaction, saturated aqueoussodium bicarbonate solution and ethyl acetate were added and the liquidwas separated. The separated organic layer was dried by adding sodiumsulfate. Next, the sodium sulfate was removed followed by distilling offthe solvent under reduced pressure and purifying by columnchromatography. 101 mg of the resulting compound were Compound (V).Yield: 90%. The ¹H-NMR data of the resulting Compound (V) coincided withthat described in Patent Document 1.

Example 4 Synthesis of Compound (V) Using Compound (IV) asSubstrate—Part 2

10 ml of xylene charged with 1.0 g of Compound (IV) and 0.72 g ofm-xylenesulfonic acid 1.9-hydrate were allowed to react for 4 hourswhile refluxing. Analysis of the resulting reaction mixture by HPLCindicated that Compound (V) had been formed in a yield of 93.6%.

Example 5 Synthesis of Compound (V) Using Compound (III) asSubstrate—Part 1

213 ml of xylene charged with 10.65 g of Compound (III) obtained inExample 1, 8.84 g of p-toluenesulfonic acid monohydrate and 4.33 g ofaniline were allowed to react for 4 hours while refluxing and removingwater. After cooling to room temperature, 198 g of water containing 2.04g of sodium hydroxide and 50 ml of ethyl acetate were added followed bystirring at 50° C. Next, an organic layer and aqueous layer wereseparated and the organic layer was concentrated under reduced pressureto obtain 13.00 g of Compound (V) as a reddish-brown syrup having apurity of 81.1% (content: 10.54 g).

On the basis of this example, it can be understood that Compound (V) canbe prepared directly from Compound (III) without isolating Compound(IV).

Example 6 Synthesis of Compound (V) Using Compound (III) asSubstrate—Part 2

795 μl of aniline and 2.0 g of Compound (III) were added to a xylenesolution charged with 838 mg of methanesulfonic acid, followed byreacting for 4 hours while refluxing and removing water. Analysis of theresulting reaction mixture by HPLC indicated that Compound (V) had beenobtained in a yield of 89.5%.

Example 7 Synthesis of Compound (V) Using Compound (III) asSubstrate—Part 3

The same reaction as Example 6 was carried out with the exception ofusing benzenesulfonic acid instead of methanesulfonic acid. Analysis ofthe resulting reaction mixture by HPLC indicated that Compound (V) hadbeen formed in a yield of 96.4%.

Example 8 Synthesis of Compound (V) Using Compound (III) asSubstrate—Part 4

The same reaction as Example 6 was carried out with the exception ofusing trifluoromethanesulfonic acid instead of methanesulfonic acid.Analysis of the resulting reaction mixture by HPLC indicated thatCompound (V) had been formed in a yield of 82.6%.

Example 9 Synthesis of Compound (V) Using Compound (III) asSubstrate—Part 5

The same reaction as Example 6 was carried out with the exception ofusing sulfuric acid instead of methanesulfonic acid. Analysis of theresulting reaction mixture by HPLC indicated that Compound (V) had beenformed in a yield of 80.3%.

Example 10 Synthesis of Compound (V) Using Compound (III) asSubstrate—Part 6

The same reaction as Example 6 was carried out with the exception ofusing p-chlorobenzenesulfonic acid instead of methanesulfonic acid.Analysis of the resulting reaction mixture by HPLC indicated thatCompound (V) had been formed in a yield of 96.0%.

Example 11 Synthesis of Compound (V) Using Compound (III) asSubstrate—Part 7

The same reaction as Example 6 was carried out with the exception ofusing 2-naphthalenesulfonic acid instead of methanesulfonic acid.Analysis of the resulting reaction mixture by HPLC indicated thatCompound (V) had been formed in a yield of 94.1%.

Example 12 Synthesis of Compound (V) Using Compound (III) asSubstrate—Part 8

The same reaction as Example 6 was carried out with the exception ofusing phosphoric acid instead of methanesulfonic acid. Analysis of theresulting reaction mixture by HPLC indicated that Compound (V) had beenformed in a yield of 64.6%.

Example 13 Synthesis of3-(3,3-dimethyl-3,4-dihydroisoquinolin-1-yl)-7-fluoroquinoline

5 ml of xylene charged with 0.23 g of Compound (III), 0.19 g ofp-toluenesulfonic acid monohydrate and 0.11 g of 3-fluoroaniline wereallowed to react for 4.5 hours while refluxing. Following completion ofthe reaction, ethyl acetate and saturated sodium bicarbonate solutionwere added followed by separating the liquid and drying the organiclayer with sodium sulfate. The sodium sulfate was removed followed bydistilling off the solvent under reduced pressure and purifying theresidue with a silica gel column to obtain 0.26 g of the title compoundas a pale yellow solid (isolated yield: 86%).

Material Data of Title Compound:

¹H-NMR (CDCl₃) δ: 9.11 (1H, d, J=2.1 Hz), 8.38 (1H, d, J=2.1 Hz),7.88-7.87 (1H, m), 7.79 (1H, dd, J=10.0, 2.4 Hz), 7.43-7.42 (1H, m),7.39-7.37 (1H, m), 7.29-7.24 (2H, m), 7.19 (1H, d, J=6.9 Hz), 2.87 (2H,s), 1.33 (6H, s).

Example 14 Synthesis of

3-(3,3-dimethyl-3,4-dihydroisoquinolin-1-yl)-7-methoxyquinoline

The same reaction as Example 13 was carried out with the exception ofusing m-anisidine instead of 3-fluoroaniline. The title compound wasobtained in an isolated yield of 99%.

Material Data of Title Compound:

¹H-NMR (CDCl₃) δ: 9.03 (1H, d, J=2.1 Hz), 8.30 (1H, d, J=2.1 Hz), 7.75(1H, d, J=8.9 Hz), 7.48 (1H, d, J=2.1 Hz), 7.42-7.41 (1H, m), 7.26-7.23(4H, m), 3.98 (3H, s), 2.86 (2H, s), 1.32 (6H, s).

Example 15 Synthesis of7-bromo-3-(3,3-dimethyl-3,4-dihydroisoquinolin-1-yl)quinoline

The same reaction as Example 13 was carried out with the exception ofusing 3-bromoaniline instead of 3-fluoroaniline. The title compound wasobtained as a yellow wax in an isolated yield of 63%.

Material Data of Title Compound:

¹H-NMR (CDCl₃) δ: 9.11 (1H, d, J=2.1 Hz), 8.35 (2H, s), 7.74 (1H, d,J=8.9 Hz), 7.67 (1H, dd, J=8.9, 1.4 Hz), 7.43 (1H, t, J=7.6 Hz),7.29-7.24 (2H, m), 7.18 (1H, d, J=7.6 Hz), 2.87 (2H, s), 1.33 (6H, s).

Example 16 Synthesis of6-bromo-3-(3,3-dimethyl-3,4-dihydroisoquinolin-1-yl)quinoline

The same reaction as Example 13 was carried out with the exception ofusing 4-bromoaniline instead of 3-fluoroaniline and changing thereaction time from 4.5 hours to 9 hours. The title compound was obtainedas a red wax in an isolated yield of 54%.

Material Data of Title Compound:

¹H-NMR (CDCl₃) δ: 9.12 (1H, d, J=2.1 Hz), 8.27 (1H, d, J=2.1 Hz),8.03-8.02 (2H, m), 7.82 (1H, dd, J=8.9, 2.1 Hz), 7.43 (1H, td, J=7.6,1.4 Hz), 7.29-7.23 (2H, m), 7.17 (1H, d, J=7.6 Hz), 2.87 (2H, s), 1.33(6H, s).

Example 17 Synthesis of3-(3,3-dimethyl-3,4-dihydroisoquinolin-1-yl)-5,7-dimethoxyquinoline

20 ml of xylene containing 1.0 g of Compound (III), 0.67 g of3,5-dimethoxyaniline and 0.83 g of p-toluenesulfonic acid monohydratewere allowed to react for 30 minutes while refluxing. 5% aqueous sodiumhydroxide solution and ethyl acetate were added followed by separatingthe liquid and drying the resulting organic layer with sodium sulfate.The sodium sulfate was removed followed by distilling off the solventunder reduced pressure and adding isopropyl ether to the residue andstirring. The precipitate was filtered out to obtain 1.33 g of the titlecompound as a white solid. Yield: 88%.

Material Data of Title Compound:

¹H-NMR (CDCl₃) δ: 9.00 (1H, d, J=2.1 Hz), 8.62 (1H, d, J=2.1 Hz),7.42-7.40 (1H, m), 7.25-7.24 (3H, m), 7.08 (1H, d, J=2.1 Hz), 6.54 (1H,d, J=2.1 Hz), 3.97 (3H, s), 3.96 (3H, s), 2.85 (2H, s), 1.32 (6H, s).

Example 18 Synthesis of3-(3,3-dimethyl-3,4-dihydroisoquinolin-1-yl)-6,7-dimethylquinoline

The same reaction as Example 13 was carried out with the exception ofusing 3,4-dimethylaniline instead of 3-fluoroaniline. The title compoundwas obtained as a yellow solid in an isolated yield of 96%.

Material Data of Title Compound:

¹H-NMR (CDCl₃) δ: 9.00 (1H, d, J=2.1 Hz), 8.24 (1H, d, J=2.1 Hz), 7.90(1H, s), 7.59 (1H, s), 7.41 (1H, td, J=7.2, 1.6 Hz), 7.27-7.18 (3H, m),2.86 (2H, s), 2.50 (3H, s), 2.46 (3H, s), 1.32 (6H, s).

Example 19 Synthesis of3-(3,3-dimethyl-3,4-dihydroisoquinolin-1-yl)-5,7-dimethylquinoline

The same reaction as Example 13 was carried out with the exception ofusing 3,5-dimethylaniline instead of 3-fluoroaniline. The title compoundwas obtained as an orange oily substance in an isolated yield of 94%.

Material Data of Title Compound:

¹H-NMR (CDCl₃) δ: 9.03 (1H, d, J=2.1 Hz), 8.45 (1H, d, J=1.4 Hz), 7.78(1H, s), 7.41 (1H, td, J=7.6, 1.4 Hz), 7.26-7.21 (4H, m), 2.87 (2H, s),2.67 (3H, s), 2.55 (3H, s), 1.34 (6H, s).

Example 20 Synthesis of3-(3,3-dimethyl-3,4-dihydroisoquinolin-1-yl)-8-methoxyquinoline

20 ml of mesitylene containing 1.0 g of Compound (III),p-toluenesulfonic acid monohydrate and 0.55 g of o-anisidine wereallowed to react for 8 hours while refluxing. 18% hydrochloric acid wasadded followed by heating and stirring at 50° C. and separating theliquid. 10% sodium hydroxide solution and ethyl acetate were added tothe resulting aqueous layer followed by separating the liquid and dryingthe organic layer with sodium sulfate. The sodium sulfate was removedfollowed by distilling off the solvent under reduced pressure andpurifying the residue with a silica gel column. 0.71 g of the titlecompound was obtained. Yield: 51%.

Material Data of Title Compound:

¹H-NMR (CDCl₃) δ: 9.06 (1H, d, J=2.1 Hz), 8.39 (1H, d, J=2.1 Hz),7.52-7.39 (3H, m), 7.27-7.26 (1H, m), 7.22 (1H, t, J=7.6 Hz), 7.17 (1H,d, J=7.6 Hz), 7.10 (1H, d, J=7.6 Hz), 4.12 (3H, s), 2.87 (2H, s), 1.33(6H, s).

Example 21 Synthesis of8-bromo-3-(3,3-dimethyl-3,4-dihydroisoquinolin-1-yl)quinoline

The same reaction as Example 20 was carried out with the exception ofusing 2-bromoaniline instead of o-anisidine. The title compound wasobtained as a brown oily substance in a yield of 21%.

Material Data of Title Compound:

¹H-NMR (CDCl₃) δ: 9.20 (1H, d, J=2.1 Hz), 8.43 (1H, d, J=2.1 Hz), 8.09(1H, dd, J=7.6, 1.4 Hz), 7.87-7.85 (1H, m), 7.44-7.43 (2H, m), 7.27-7.20(3H, m), 2.87 (2H, s), 1.33 (6H, s).

Example 22 Synthesis of Compound (III)—Part 2

910 ml of a xylene solution containing 91.55 g of DMF were cooled to 2°C. followed by blowing 109.2 g of phosgene over the course of 30minutes. After stifling for 30 minutes at room temperature, 140 ml ofxylene containing 70.0 g of Compound (I) were added dropwise. Next, thetemperature was raised to 90° C. followed by stirring for 5 hours. Aftercooling to 45° C., 595 ml of water were added and stirred. Analysis ofthe reaction mixture by HPLC indicated that 127.29 g of Compound (II)had formed (reaction yield: 98.5%).

286.52 g of water containing 71.63 g of sodium hydroxide were droppedinto the aforementioned reaction mixture followed by stifling for 5hours at 90° C. After cooling to 30° C., insoluble material was removedfollowed by liquid separation. Analysis of the resulting xylene layer byHPLC indicated that 82.57 g of Compound (III) were contained (reactionyield: 90.5%).

Example 23 Synthesis of Compound (II)—Part 1

A xylene solution containing 9.99 g of phosgene was dropped into 105 mlof xylene containing 9.15 g of DMF and 7.0 g of Compound (I) over thecourse of 20 minutes. Next, the temperature was raised to 90° C.followed by stirring for 5 hours at the same temperature. After coolingto 45° C., 119 ml of water were added dropwise and stirred. Measurementof the resulting reaction mixture by HPLC indicated that 12.41 g ofCompound (II) had formed. Reaction yield: 96.0%.

Example 24 Synthesis of Compound (II)—Part 2

The same reaction as Example 23 was carried with the exception of usingbutyl acetate instead of xylene. Compound (II) was formed in a reactionyield of 93.2%.

Example 25 Synthesis of 2p-toluenesulfonate Salt of Compound (V)

10.01 g of Compound (III), 4.28 g of aniline and 100.39 g of xylene weremixed followed by stifling for 1 hour at 140° C. A xylene solution ofp-toluenesulfonic acid prepared by heating 18.38 g of p-toluenesulfonicacid monohydrate and 50.69 g of xylene to 140° C. while dehydrating wascharged into this heated solution followed by stifling for 4 hours at140° C. Following completion of the reaction, the reaction liquid wascooled to 70° C. followed by the addition of 39.35 g of isopropanolthereto and refluxing for 1 hour at 85° C. to 88° C. After cooling toroom temperature, the precipitated solid was filtered out and furtherwashed with 71.95 g of xylene. The resulting solid was dried underreduced pressure to obtain 25.78 g of the title compound as a paleyellow solid (yield: 93.6%).

Material Data of Title Compound:

Melting point: 235° C. to 236° C.

¹H-NMR (DMSO-d6) δ ppm: 1.53 (6H, s), 2.29 (6H, s), 3.35 (2H, s), 7.12(4H, dd, J=0.6, 8.6 Hz), 7.47 (4H, dd, J=0.6, 8.6 Hz), 7.53 (1H, td,J=1.2, 8.0 Hz), 7.57 (1H, dd, J=1.2, 8.0 Hz), 7.62 (1H, d, J=7.3 Hz),7.83 (1H, ddd, J=1.2, 6.9, 8.3 Hz), 7.89 (1H, td, J=1.2, 7.3 Hz), 8.04(1H, ddd, J=1.2, 6.9, 8.3 Hz), 8.23 (1H, d, J=8.3 Hz), 8.25 (1H, d,J=8.3 Hz), 8.92 (1H, d, J=2.1 Hz), 9.14 (1H, d, J=2.1 Hz), 13.25 (2H,brs).

Example 26 Hexafluorophosphate Salt of Compound (II)

63.0 g of DMF were cooled to 5° C. followed by dropping 16.12 g ofoxalyl chloride therein while keeping the temperature lower than 10° C.After stifling for 30 minutes, 10.0 g of Compound (I) were droppedtherein while keeping the temperature lower than 10° C. Followingcompletion of the dropping, the reaction mixture was heated to 70° C.and stirred for 3 hours. Analysis by HPLC at this time indicated thatCompound (II) had been formed in a yield of 98.5%. The reaction liquidcooled to 30° C. and 5 mol/L of an aqueous sodium hydroxide solution(34.6 mL) were simultaneously added dropwise into an aqueous solution ofpotassium hexafluorophosphate (11.69 g) cooled to 5° C. while keepingthe temperature lower than 10° C. The resulting precipitate was filteredout followed by drying under reduced pressure to obtain 12.60 g of ayellow solid (yield: 53.6%).

Material Data of Title Compound:

Melting point: 172° C. to 176° C.

¹H-NMR (CDCl₃) δ: 7.73 (2H, s), 7.46 (1H, td, J=7.2, 1.4 Hz), 7.41 (1H,t, J=7.2 Hz), 7.34 (1H, dd, J=7.6, 1.4 Hz), 7.24 (1H, d, J=6.9 Hz), 3.35(6H, s), 2.85 (6H, s), 2.77 (2H, s), 1.29 (6H, s).

Example 27 Synthesis from Compound (I) to Compound (V)

40.70 g of phosphoryl chloride were dropped into a solution cooled to 1°C. obtained by mixing 24.05 g of DMF with 223.17 g of xylene whilekeeping the temperature lower than 10° C. followed by stifling for 30minutes. A mixed solution of 18.39 g of Compound (I) and 34.33 g ofxylene was dropped therein followed by heating to 90° C. After stiflingfor 20 hours at 90° C., the reaction liquid was dropped into 240.64 g of20% aqueous sodium hydroxide solution cooled to 2° C. Next, thetemperature was raised to 60° C. under reduced pressure (160 mmHg to 200mmHg) followed by stifling for 6 hours while removing the aqueousdimethylamine solution formed by the reaction using a Dean-Stark tube.After cooling the reaction liquid to room temperature, insolublematerial was filtered out followed by liquid separation of the filtrate.Analysis of the organic layer by HPLC confirmed that Compound (III) hadbeen formed in a reaction yield of 89.5%. 9.27 g of aniline and 40.83 gof xylene were added to the resulting organic layer followed by heatingto 140° C. and stirring for 1 hour. 107.11 g of xylene charged with39.67 g of p-toluenesulfonic acid in the uniform state by heating andstirring at 140° C. were dropped therein followed by stirring for 3hours at the same temperature. After cooling to 85° C., 87.0 g ofisopropanol were added followed by stirring for 1 hour. The solid wasfiltered out after cooling to 25° C. and stifling for 2 hours. Theresulting solid was dried to obtain 56.48 g of 2p-toluenesulfonate saltof Compound (V) as a yellow solid (purity: 98.4%).

491.82 g of chlorobenzene and 500 g of 1.5% aqueous sodium hydroxidesolution were added to 50.00 g of the 2p-toluenesulfonate salt ofCompound (V) followed by stifling for 1 hour at room temperature. Theorganic layer obtained by a liquid separation procedure was dehydratedat 45° C. under reduced pressure to obtain 486.01 g of a chlorobenzenesolution containing Compound (V). Measurement by HPLC indicated that thecontent of Compound (V) was 21.82 g.

INDUSTRIAL APPLICABILITY

According to the present invention, 3,4-dihydroisoquinoline derivativescan be provided efficiently by a simple procedure. Moreover, the presentinvention has high value in terms of industrial use since it enablesindustrial production to be carried out advantageously.

1. A compound represented by formula (3):

wherein R1 and R2 independently represent an optionally substitutedalkyl group having 1 to 6 carbon atoms, or R1 and R2 together with thecarbon atom to which they are bound form an optionally substitutedcycloalkyl group having 3 to 10 carbon atoms, X represents a halogenatom, optionally substituted alkyl group having 1 to 6 carbon atoms oroptionally substituted alkoxy group having 1 to 6 carbon atoms, and nrepresents an integer of 0 to
 4. 2. The compound represented by formula(3) according to claim 1, wherein R1 and R2 independently represent anoptionally substituted alkyl group having 1 to 6 carbon atoms.
 3. Thecompound represented by formula (3) according to claim 2, wherein n is0.
 4. A method for producing a compound represented by formula (3) asdefined in claim 1: comprising hydrolyzing a salt containing a compoundrepresented by formula (5):

wherein R1, R2, X and n are the same as previously defined, and R3 is analkyl group having 1 to 3 carbon atoms, to obtain the compoundrepresented by formula (3).
 5. The method for producing a compoundrepresented by formula (3) according to claim 4, wherein R1 and R2independently represent an optionally substituted alkyl group having 1to 6 carbon atoms.
 6. The method for producing a compound represented byformula (3) according to claim 5, wherein n is
 0. 7. A method forproducing a compound represented by formula (2):

wherein R1 and R2 independently represent an optionally substitutedalkyl group having 1 to 6 carbon atoms, or R1 and R2 together with thecarbon atom to which they are bound form an optionally substitutedcycloalkyl group having 3 to 10 carbon atoms, X represents a halogenatom, optionally substituted alkyl group having 1 to 6 carbon atoms oroptionally substituted alkoxy group having 1 to 6 carbon atoms, and nrepresents an integer of 0 to 4, Y represents a halogen atom, optionallysubstituted alkyl group having 1 to 6 carbon atoms or optionallysubstituted alkoxy group having 1 to 6 carbon atoms, and m represents aninteger of 0 to 4, comprising reacting a compound represented by formula(3):

wherein R1, R2, X and n are the same as defined in formula (2), with acompound represented by formula (4):

wherein Y and m are the same as previously defined, to obtain thecompound represented by formula (2).
 8. The method for producing acompound represented by formula (2) according to claim 7, wherein R1 andR2 independently represent an optionally substituted alkyl group having1 to 6 carbon atoms.
 9. The method for producing a compound representedby formula (2) according to claim 8, wherein n is
 0. 10. A compoundrepresented by formula (2):

wherein R1 and R2 independently represent an optionally substitutedalkyl group having 1 to 6 carbon atoms, or R1 and R2 together with thecarbon atom to which they are bound form an optionally substitutedcycloalkyl group having 3 to 10 carbon atoms, X represents a halogenatom, optionally substituted alkyl group having 1 to 6 carbon atoms oroptionally substituted alkoxy group having 1 to 6 carbon atoms, and nrepresents an integer of 0 to 4, Y represents a halogen atom, optionallysubstituted alkyl group having 1 to 6 carbon atoms or optionallysubstituted alkoxy group having 1 to 6 carbon atoms, and m represents aninteger of 0 to
 4. 11. The compound represented by formula (2) accordingto claim 10, wherein R1 and R2 independently represent an optionallysubstituted alkyl group having 1 to 6 carbon atoms.
 12. The compoundrepresented by formula (2) according to claim 11, wherein n is
 0. 13. Asalt containing a compound represented by formula (5):

wherein R1 and R2 independently represent an optionally substitutedalkyl group having 1 to 6 carbon atoms, or R1 and R2 together with thecarbon atom to which they are bound form an optionally substitutedcycloalkyl group having 3 to 10 carbon atoms, R3 is an alkyl grouphaving 1 to 3 carbon atoms, X represents a halogen atom, optionallysubstituted alkyl group having 1 to 6 carbon atoms or optionallysubstituted alkoxy group having 1 to 6 carbon atoms, and n represents aninteger of 0 to
 4. 14. The salt containing a compound represented byformula (5) according to claim 13, wherein R1 and R2 independentlyrepresent an optionally substituted alkyl group having 1 to 6 carbonatoms.
 15. The salt containing a compound represented by formula (5)according to claim 13, wherein n is
 0. 16. A method for producing a saltcontaining a compound represented by formula (5) as defined in claim 13:comprising reacting a compound represented by formula (6):

wherein R1, R2, X and n are the same as previously defined, with a saltcontaining a compound represented by formula (7):

wherein R3 is the same as previously defined, and Z represents a halogenatom, to obtain the salt containing a compound represented by formula(5).
 17. The method for producing a salt containing a compoundrepresented by formula (5) according to claim 16, wherein R1 and R2independently represent an optionally substituted alkyl group having 1to 6 carbon atoms.
 18. The method for producing a salt containing acompound represented by formula (5) according to claim 17, wherein n is0.